The present invention relates to derivatives of pyrimido[6,1-a]isoquinolin-4-one and their application as inhibitors of phosphodiesterase (PDE) isoenzymes. More particularly the invention relates to derivatives of pyrimido[6,1-a]isoquinolin-4-one and their use in medicine for example as bronchodilators with anti-inflammatory properties.
In all cells where cyclic AMP (cAMP) is present as a secondary messenger, intracellular concentrations of cAMP are regulated by the two processes involved in its formation and degradation. Stimulation of membrane bound receptors on the external surface of the cells (e.g. by xcex2-adrenoceptor agonists) results in activation of adenylyl cyclase to generate cAMP from ATP. Phosphodiesterases present in the cell serve to reduce the concentration of cAMP by hydrolysing it to adenosine monophosphate (AMP).
In a disease such as asthma, the principal cells involved in the associated bronchoconstriction and inflammatory processes are subject to inhibitory control by cAMP. Inhibitors of type III phosphodiesterase raise intracellular levels of cAMP, leading to relaxation of bronchial smooth muscle, whereas inhibitors of type IV phosphodiesterase inhibit the release of damaging mediators from pro-inflammatory cells. Thus, in principle, a combined PDE III/V inhibitor should have the desirable effects of a xcex2-adrenoceptor agonist plus an inhaled anti-inflammatory steroid which are currently the mainstay of treatment in severe asthma. Moreover, a combined PDE III/IV inhibitor given by inhalation should achieve beneficial effects similar to a xcex2-agonist plus inhaled steroid and should be an unusually effective treatment of asthma and other respiratory disorders without the undesirable glucocorticoid effects of the steroid such as osteoporosis and the stunting of growth.
The potential adverse effects of a PDE III/IV inhibitor (e.g., nausea and vomiting, gastric acid secretion, cardiovascular effects such as increase cardiac contractility, vasodilation and potential arrhythmogenic activity) should be avoidable with a compound that is directly delivered to the lungs by inhalation. It is desirable that the substance is long acting and non-irritant.
An example of a pyrimido[6,1-a]isoquinolin-4-one derivative with PDE III/IV inhibitory activity and known to possess antihypertensive vasodilator activity is trequinsin (9,10-dimethoxy-3-methyl-2-mesitylimino-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one), which is described by De Souza et al., J. Med. Chem. 27 1470-1480 (1984) and in GB-A-1597717.
As described by De Souza et al. and in GB-A-1597717, trequinsin has valuable pharmacological properties, and can be administered to human subjects suffering from, for example, respiratory disorders. However, it is unsuitable for administration by inhalation because in vitro data indicate its persistence of action is less than desirable.
It has now been found that it is possible to design certain pyrimido [6,1-A] isoquinolin-4-one derivatives which are PDE inhibitors, which have a longer duration of action relative to trequinsin.
According to a first aspect of the present invention there is provided a compound of general formula I: 
wherein
each of R1 and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group; each of R7 and le independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy, C3-6 cycloalkyl; and
R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
each of R10 and R11 independently represents a hydrogen atom, a C1-3 alkyl, C3-6 cycloalkyl or phenyl group;
Y represents an oxygen atom or a group CHNO2, NCN, NH or NNO2;
n is an integer from 2 to 4;
or a salt thereof.
As used herein the term xe2x80x9chalogenxe2x80x9d or its abbreviation xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo or iodo.
As used herein the term xe2x80x9cC1-6 alkylxe2x80x9d refers to straight chain or branched chain alkyl groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl. C1-4 alkyl groups are preferred.
As used herein the term xe2x80x9cC2-3 alkenylxe2x80x9d refers to straight chain or branched chain hydrocarbon groups having from two to three carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include for example, vinyl and 1-propenyl.
As used herein the term xe2x80x9cC2-3 alkynylxe2x80x9d refers to straight chain hydrocarbon groups having from two to three carbon atoms and having in addition one triple bond. This term would include for example, ethynyl and 1-propynyl.
As used herein the term xe2x80x9cC2-6 alkenylxe2x80x9d refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl. C2-3 alkenyl groups are preferred.
As used herein the term xe2x80x9cC2-6 alkynylxe2x80x9d refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentanyl, 3-pentanyl, 4-pentanyl, 2-hexanyl, 3-hexanyl, 4-hexanyl and 5-hexanyl. C2-3 alkynyl groups are preferred.
As used herein the term xe2x80x9cC1-6 alkoxyxe2x80x9d refers to straight chain or branched chain alkoxy groups having from one to six carbon atoms. Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy and hexoxy. C1-4 a alkoxy groups are preferred.
As used herein the term xe2x80x9cC2-7 acylxe2x80x9d refers to straight chain or branched chain acyl groups having from two to seven carbon atoms. Illustrative of such acyl groups are acetyl, propionyl (or propiono or propanoyl), isopropionyl (or isopropiono or isopropanoyl), butyryl (or butanoyl), isobutyryl (or isobutanoyl), pentanoyl (or valeryl), hexanoyl (or capronyl) and heptanoyl.
As used herein the term xe2x80x9cC2-7 acyloxyxe2x80x9d refers to straight chain or branched chain acyloxy groups having from two to seven carbon atoms. Illustrative of such acyloxy groups are acetyloxy, propionyl (or propiono or propanoyl)oxy, isopropionyl (or isopropiono or isopropanoyl)oxy, butyryl (or butanoyl)oxy, isobutyryl (or isobutanoyl)oxy, pentanoyl (or valeryl)oxy, hexanoyl (or capronyl)oxy and heptanoyloxy. C2-4 acyloxy groups are preferred.
As used herein the term xe2x80x9cC3-6 cycloalkylxe2x80x9d refers to an alicyclic group having from three to six carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopentyl and cyclohexyl groups are preferred.
As used herein the term xe2x80x9cC1-6 alkylthioxe2x80x9d refers to straight chain or branched chain alkylthio groups having from one to six carbon atoms. Illustrative of such alkylthio groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, neopentylthio and hexylthio. C1-4 alkylthio groups are preferred.
As used herein the term xe2x80x9cC1-6 alkylaminoxe2x80x9d refers to straight chain or branched chain alkylamino groups having from one to six carbon atoms. Illustrative of such alkylamino groups are methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, neopentylamino and hexylamino. C1-4 alkylamino groups are preferred.
As used herein, the term xe2x80x9cdi(C1-6) alkylaminoxe2x80x9d refers to straight chain or branched chain di-alkylamino groups having from one to six carbon atoms in each of the alkyl groups. Illustrative of such dialkylamino groups are di-methylamino, di-ethylamino, di-propylamino, di-isopropylamino, di-butylamino, di-isobutylamino, di-sec-butylamino, di-tert-butylamino, di-pentylamino, di-neopentylamino and di-hexylamino. Di(C1-4)alkylamino groups are preferred.
As used herein, the term xe2x80x9cC2-7 acylaminoxe2x80x9d refers to straight chain or branched chain acylamino groups having from two to seven carbon atoms. Illustrative of such acylamino groups are acetylamino, propionyl (or propiono or propanoyl)amino, isopropionyl (or isopropiono or isopropanoyl)amino, butyryl (or butanoyl)amino, isobutyryl (or isobutanoyl)amino, pentanoyl (or valeryl)amino, hexanoyl (or capronyl)amino and heptanoylamino. C2-4 acylamino groups are preferred.
Where there is a substituent which renders a compound basic, for example when R6 is an amino, alkylamino or dialkylamino group, addition of an acid results in a salt. The acid may be any suitable acid, and can be organic or inorganic.
Preferred compounds of general formula I include those in which, independently or in any compatible combination:
each of R1 and R2 represents a C1-6 alkyl, preferably a C1-4 alkyl, group;
R1 and R2 are the same as each other;
each of R3 and R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a hydrogen atom;
each of R7 and R8 represents a C1-6 alkyl, preferably methyl, ethyl or isopropyl, group;
R7 and R8 are the same as each other,
R9 represents a hydrogen atom, a halogen atom or a methyl or acetyl group;
Y represents an oxygen atom or a group CHNO2; and
n is 2.
Exemplary compounds include:
1. 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one;
2. 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-[N-(Nxe2x80x2-isopropylcarbamoyl) 2-aminoethyl]-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one;
3. 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-[N-[1-(Nxe2x80x2-methyl-2-nitroethenamine)]-2-aminoethyl]-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]-isoquinolin-4-one;
4. 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-[N-[1-(N-isopropyl-2-nitroethenamine)]-2-aminoethyl]-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]-isoquinolin-4-one;
5. 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-[N[1-(Nxe2x80x2,Nxe2x80x2-dimethyl-2-nitroethenamine)]-2-aminoethyl]-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]-isoquinolin-4-one;
6. 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-[N-(Nxe2x80x2-phenylcarbamoyl)-2-aminoethyl]-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-2-one;
7. 9,10-Dimethoxy-3-[2-guanidinoethyl]-2-(2,4,6-trimethylphenylimino)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one;
8. 9,10-Dimethoxy-3-[N-(Nxe2x80x2-nitro)-2-guanidinoethyl]-2-(2,4,6-trimethylphenylimino)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one;
9. 3-[N-(Nxe2x80x2-Cyclohexylcarbamoyl)-2-aminoethyl]-9,10-dimethoxy-2-(2,4,6-trimethyl-phenylimino3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one;
10. 3-(N-Carbamoyl-2-aminoethyl)-9,10-dimethoxy-2-(2-methylphenylimino)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one;
11 3N-Carbamoyl-2-aminoethyl)-2-(2,6-diisopropylphenylimino)-9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one;
12. 3-(N-Carbamoyl-4-aminobutyl)-9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one;
13. 3-[N-(Nxe2x80x2-Cyano-Nxe2x80x3-methyl)-2-guanidinoethyl]-9,10-dimethoxy-2-(2,4,6-trimethyl-phenylimino)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin 4-one.
The compound: 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl aminoethyl)-3,4,6,7 tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one is particularly preferred.
Compounds of general formula I may be prepared by any suitable method known in the art and/or by the following process, which itself forms part of the invention.
According to a second aspect of the invention, there is provided a process for preparing a compound of general formula I as defined above, the process comprising:
(a) derivatising a compound of general formula II: 
wherein R1, R2, R5, R6, R7, R8, R9, X and n are as defined for general formula I, with one or more compounds capable of reacting at the primary amine group of the aminoalkyl moiety (xe2x80x94(CH2)nxe2x80x94NH2), to form a compound of general formula I; or
(b) when X in general formula I represents a group CR3R4, wherein R3 represents a hydrogen atom, R4 represents a hydrogen atom or a C1-3 alkyl group, and R5 represents a hydrogen atom or a C1-3 alkyl group, hydrogenating a compound of general formula III: 
wherein R1, R2, R6, R7, R8, R9, R10, R11, Y and n are as defined for general formula I; and
(c) optionally converting a compound of general formula I so formed into another compound of general formula I.
The reaction conditions of step (a) are generally such as to favour the reaction, which may be a nucleophilic displacement or addition and is carried out in a solvent which is suitable for the particular reaction.
Compounds chosen for reacting with a compound of general formula II are capable of reacting at the primary amine group of the alkylamino moiety in the compound of general formula II, to form a compound of general formula I. For example:
when Y represents an oxygen atom and each of R10 and R11 represents a hydrogen atom, a compound of general formula II may be derivatised with sodium cyanate;
when Y represents an oxygen atom, R10 represents a hydrogen atom and R11 represents a C1-3 alkyl, C3-6 cycloalkyl or phenyl group, a compound of general formula II may be derivatised with an isocyanate of the general formula R11NCO;
when Y represents CHNO2, R10 represents a hydrogen atom and R11 represents a C1-3 alkyl or C3-6 cycloalkyl group, a compound of general formula II may be derivatised with an Nxe2x80x94C1-3 alkyl- or Nxe2x80x94C3-6 cycloalkyl-1-(methylthio)-2-nitroethenamine of the general formula CH3SC(xe2x95x90CHNO2)NR10R11;
when Y represents CHNO2, a compound of general formula II may be reacted first with 1,1-bis(methylthio)-2-nitroethylene and the resulting compound may then be reacted with an amine of the general formula R10R11NH, wherein R10 and R11 are as defined for general formula I;
when Y represents NH, a compound of general formula II may be derivatised with a compound of general formula CH3SC(xe2x95x90NH)NR10R11 or a salt thereof, wherein R10 and R11 are as defined for general formula I; and
when Y represents NCN, a compound of general formula II may be derivatised with a compound of general formula CH3SC(xe2x95x90NCN)NR10R11 or a salt thereof, wherein R10 and R11 are as defined for general formula I.
In specific cases:
for 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one, sodium cyanate may be chosen;
for 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-[N-(Nxe2x80x2-isopropylcarbamoyl)-2-aminoethyl]-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one, isopropylisocyanate may be chosen;
for 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-[N-[1-(Nxe2x80x2-methyl-2-nitroethenamine)]-2-aminoethyl]-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]-isoquinolin-4-one, N-methyl-1-(methylthio)-2-nitroethenamine may be chosen;
for 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-[N-[1-(M-isopropyl-2-nitroethenamine)]-2-aminoethyl]-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]-isoquinolin-4-one, 1,1-bis(methylthio)-2-nitroethylene and isopropylamine may be chosen;
for 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-[N-[1-(Nxe2x80x2,Nxe2x80x2-dimethyl-2-nitroethenamine)]-2-aminoethyl]-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]-isoquinolin-4-one, 1,1-bis(methylthio)-2-nitroethylene and dimethylamine may be chosen; and
for 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-[N-(Nxe2x80x2-phenylcarbamoyl)-2-aminoethyl]-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-2-one, phenylisocyanate may be chosen.
Compounds of general formula II may be prepared by reacting a compound of general formula IV: 
wherein R1, R2, R5, R6, R7, R8, R9 and X are as defined for general formula 1, with a compound of general formula V:
LGxe2x80x94(CH2)nxe2x80x94Nxe2x80x94PGxe2x80x83xe2x80x83V 
wherein n is as defined for general formula I, LG represents a leaving group, and PG represents a protecting group; and then removing the protecting group.
The reaction between a compound of general formula IV and a compound of general formula V is generally carried out in suitable conditions for the reaction, which is a nucleophilic substitution. A base such as K2CO3 may be used in the presence of NaI and the reaction is performed in a suitable solvent such as 2-butanone.
The leaving group LG in general formula V may be any suitable leaving group, but is preferably a halogen atom, such as bromine. The protecting group PG in general formula V may be any suitable protecting group, such as a phthaloyl group. If the reaction between a compound of general formula IV and V is carried out in a base such as K2CO3, the protecting group should be base-stable. A suitable compound of general formula V is N-(2-bromoethyl)phthalimide: 
The protecting group may then be removed by standard deprotection procedures. For example, hydrazine hydrate may be used. The reaction conditions are generally to favour the reaction, for example in a suitable solvent such as ethanol and/or chloroform at room temperature.
Compounds of general formula IV may be prepared by reacting a compound of general formula VI: 
wherein R1, R2, R5, R6 and X are as defined for general formula I and LG represents a leaving group; with a compound of general formula VII: 
wherein R7, R8 and R9 are as defined for general formula I.
Compounds of general formula VII are substituted anilines which are either known in the art and available from commercial sources or may readily be prepared by methods known per se.
The leaving group LG in compounds of general formula VI may be chlorine, a thioalkyl group, preferably thiomethyl, or an alkylsulphonyl group, preferably methylsulphonyl. Preferably it is chlorine.
The reaction conditions are generally such as to favour the reaction, which is a nucleophilic displacement which is preferably carried out in a suitable solvent such as dimethylformamide or isopropanol in the presence of a base such as potassium carbonate. Suitable reaction conditions may be found in GB-A-1597717 and EP-A-0124893, which disclose the preparation of related compounds.
The reaction is generally applicable for producing compounds of general formula I where R6 represents a hydrogen atom or a C1-6 alyl, C26 alkenyl, C2-6 alkynyl, amino, C1-4 alkylamino or C2-7 acylamino group and R1 to R5 and R7 to R9, X, Y and n have the meanings given above.
Compounds of general formula VI where LG represents a chlorine atom may be prepared by reacting a compound of general formula VIII or a compound of general formula IX with phosphorous oxychloride, or by heating a compound of general formula VIII with phosphorous pentachloride: 
wherein R1, R2, R5 and R6 and X are as defined for general formula I. Compounds of general formula VI where LG represents a thioalkyl group may be prepared from compounds of formula VIII by heating with phosphorous pentasulphide in a solvent such as dioxan or pyridine to give initially the intermediate thio derivative of VIII which, on treatment with an alkylating agent such as an alkyl iodide eg. methyl iodide, in a suitable solvent such as tetrahydrofuran or ethyl acetate, gives the thioalkyl compound. Oxidation of the thioalkyl compound with, for example, 3-chloroperbenzoic acid in a solvent such as methylene chloride, gives the alklylsulphone derivative.
Compounds of general formula VIII may be prepared by reacting a compound of general formula IX, wherein R1, R2, R5 and R6 are as defined for general formula I, with a cyclodehydrating agent such as phosphorous oxychloride, under less vigorous condition, ie lower temperatures, than those required to give compounds of the general formula VI where LG represents a chlorine atom. An alternative method has been described in NL-A-6,401,827 (Hoffmann-La Roche) which involves reacting the carbamoylmethylene-tetrahydroisoquinoline, general formula XI (wherein R1, R2, R5 and X have the meanings given above) with diethyl carbonate in ethanolic sodium ethoxide: 
Compounds of general formula IX may be prepared by reacting a compound of general formula XII 
wherein R1, R2, R5 and X are as defined for general formula I, with R6CH(CO,Et)2, wherein R6 is as defined for general formula I, and a strong base such as sodium ethoxide in a hot ethanolic solution. Alternatively, the corresponding dimethyl ester can be employed in the presence of hot methanolic sodium methoxide.
Compounds of general formula XII may be prepared by reacting a compound of general formula XIII: 
wherein R1, R2, R5 and X are as defined for general formula I, with urea by heating at 160xc2x0 C. Alternatively, compounds of general formula XIII may be reacted with potassium cyanate in the presence of acetic acid in a suitable solvent such as ethanol.
Compounds of general formula XIII are either known in the art or may readily be prepared by methods known per se. For example, the preparation of 1-(3,4 dimethoxyphenethyl)barbituric acid has been described by B. Lal et al. in J. Med. Chem. 27 1470-1480 (1984).
Turning to step (b), the reaction conditions of step (b) are generally to favour the hydrogenation reaction, and the reaction is generally carried out in a suitable solvent such as an alcohol, eg ethanol, with a noble metal catalyst such as palladium, platinum, rhodium or nickel, at room temperature. The catalyst may be supported, for example on charcoal or alumina.
Compounds of general formula III may be prepared from a compound of general formula XIV: 
wherein R1, R2 and R6 are as defined for general formula I, and R4 and R5 independently represent a hydrogen atom or a C1-3 alkyl group. The reactions are conducted as described above for converting a compound of general formula VIII to a compound of general formula II through compounds of general formula VI and general formula IV, and the preferred reaction conditions correspond accordingly.
Compounds of general formula XIV may be prepared from compounds of general formula VIII (wherein X represents a CH2 group and R5 represents a hydrogen atom or a C1-3 alkyl group) by heating with a noble metal catalyst such as palladium, platinum, rhodium or nickel at a temperature of 300 to 350xc2x0 C. The catalyst may be supported on charcoal or alumina and the reaction carried out in an inert solvent such as an aromatic hydrocarbon, eg p-cymene.
In optional step (c), a compound of general formula I may be converted into another compound of general formula I. For example, compounds of general formula I where R6 represents NH2 may be converted into compounds of general formula I where R6 represents a C1-6 alkylamino group by standard chemistry, such as by alkylation of a protected derivative such as an acyl or a p-toluenesulphonyl derivative followed by removal of the protecting group, such as by acid hydrolysis. Compounds of general formula I where R6 represents a di(C1-6) alkylamino group may be prepared by direct alkylation of the alkylamino derivative. Compounds of general formula I wherein R5, R6, R7, R8 and/or R9 represent a C2-3 alkenyl, C2-6 alkenyl, C2-3 alkynyl or C2-6 alkynyl group may be hydrogenated to give the corresponding compound with saturated bonds. The reaction conditions for the hydrogenation are as outlined above for step (b).
According to a third aspect, the present invention provides a composition comprising a compound of general formula I and a veterinarily or pharmaceutically acceptable carrier or diluent. Preferably the composition is a pharmaceutical composition for human medicine.
Compounds of the present invention are PDE inhibitors and thus possess valuable pharmacological properties, such as bronchodilator activity as demonstrated by the inhibition of field-stimulated contraction of guinea-pig isolated trachea, and anti-inflammatory activity as illustrated in studies on human mononuclear cells stimulated by PHA (phytohaemagglutinin). In vitro and in vivo data indicate the compounds have a long duration of action, as demonstrated by their persistent protective effects against histamine induced bronchospasm in the guinea-pig when inhaled directly into the lungs as a dry powder. The invention therefore also relates to acute, chronic or prophylactic treatment of patients suffering from respiratory disorders including, in particular, asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), and cystic fibrosis. They may also be used topically in skin disorders such as atopic dermatitis and psoriasis, or in ocular inflammation or any other disease including cerebral ischaemia or auto-immune diseases in which increasing intracellular concentrations of cAMP is considered beneficial.
One or more compounds as set out in the first aspect of the invention may be present in association with one or more non-toxic pharmaceutically and/or veterinarily acceptable carriers and/or diluents and/or adjuvants and/or propellants and, if desired, other active ingredients. Suitable carriers or diluents are known in the art (eg Handbook of Pharmaceutical Excipients (1994)2nd Edition, Eds. A. Wade/PJ Weller, The Pharmaceutical Press, American Pharmaceutical Association).
Preferably, the compounds and the compositions of the present invention are administered by inhalation, for example by aerosols or sprays which can disperse the pharmacological active ingredient in the form of a powder or in the form of a solution or suspension. Pharmaceutical compositions with powder-dispersing properties usually contain, in addition to the active ingredient, a liquid propellant with a boiling point below room temperature and, if desired, adjuncts, such as liquid or solid nonionic or anionic surfactants and/or wetting agent to form a stable dispersion. Pharmaceutical compositions in which the pharmacological active ingredient is in solution contain, in addition to this, a suitable propellant, and furthermore, if necessary, an additional solvent and/or a stabiliser. Instead of the propellant, compressed air can also be use, it being possible for this to be produced as required by means of a suitable compression and expansion device. Pharmaceutical compositions may also be delivered by breath activated inhalation devices. Dry powder compositions are preferred for administration by inhalation.
According to a fourth aspect, the present invention provides a compound of general formula I or a composition containing a compound of general formula I for use in medicine. Compounds of the present invention are useful as inhibitors of phosphodiesterase isoenzymes. The compounds or compositions of the present invention may be used to prevent or treat any disease in which the compounds or compositions are useful, but particularly a disease in which raising the intracellular concentration of cAMP is desirable. Examples of diseases against which compounds are useful include respiratory disorders including, in particular, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), allergic asthma, hay fever, allergic rhinitis, and cystic fibrosis. They may also be used topically in skin disorders such as atopic dermatitis or psoriasis, ocular inflammation, or any other disease including cerebral ischaemia or auto-immune diseases in which increasing intracellular concentrations of cAMP is considered beneficial.
This aspect of the invention is particularly relevant to the treatment of humans, but is also applicable to general veterinary industry, in particular domestic animals such as dogs and cats and farm animals such as horses, pigs, cattle, sheep, etc.
Dosage levels of the order of about 0.02 mg to about 200 mg, to be taken up to three times daily, are useful in the treatment of the above-mentioned conditions. More particularly, a dosage range of about 0.2 mg to about 20 mg, taken up to three times daily, is effective. The particular dosage regime will however ultimately be determined by the attending physician and will take into consideration such factors as the medication being used, age, weight, severity of symptoms and/or severity of treatment being or to be applied, method of administration of the medication, adverse reactions and/or other contraindications.
The medication according to this aspect of the invention may be given to a patient together with other active agents, which may for example be a different compound of the present invention, or other compounds. Examples include xcex22-adrenoceptor agonists, topical glucocorticoid steroids, xanthine derivatives, antihistamine compounds, leukotriene antagonists, inhibitors of leukotriene synthesis and/or combinations thereof.
According to a fifth aspect, the present invention provides the use of a compound of general formula I in the manufacture of an inhibitor of a type III/IV phosphodiesterase isoenzyme. The invention encompasses the use of a compound of general formula I in the manufacture of a bronchodilator and/or an anti-asthmatic medication and/or a medicament for the prevention or treatment of chronic obstructive pulmonary disease (COPD).
The invention also relates to a method for the treatment or prevention of a disease in a mammal where a phosphodiesterase isoenzyme inhibitor and/or a bronchodilator would be expected to be of benefit, which method comprises administering to said mammal an amount of an effective, non-toxic amount of a compound of general formula I. The invention encompasses a method of treating or preventing asthma and/or chronic obstructive pulmonary disease (COPD) in a mammal.
Preferred features of each aspect of the invention apply to each other aspect of the invention, mutatis mutandis.